The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivate VCP in murine postnatal forebrain neurons (VCP conditional knockout [cKO]). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulates features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.Glutamatergic and GABAergic synaptic transmission controls excitation and inhibition of postsynaptic neurons, whereas activity of ion channels modulates neuronal intrinsic excitability. However, it is unclear how excessive neuronal excitation affects intrinsic inhibition to regain homeostatic stability under physiological or pathophysiological conditions. Here, we report that a seizure-like sustained depolarization can induce short-term inhibition of hippocampal CA3 neurons via a mechanism of membrane shunting. This depolarization-induced shunting inhibition (DShI) mediates a non-synaptic, but neuronal intrinsic, short-term plasticity that is able to suppress action potential generation and postsynaptic responses by activated ionotropic receptors. We demonstrate that the TRESK channel significantly contributes to DShI. Disruption of DShI by genetic knockout of TRESK exacerbates the sensitivity and severity of epileptic seizures of mice, whereas overexpression of TRESK attenuates seizures. In summary, these results uncover a type of homeostatic intrinsic plasticity and its underlying mechanism. TRESK might represent a therapeutic target for antiepileptic drugs.The process of pyroptosis is mediated by inflammasomes and a downstream effector known as gasdermin D (GSDMD). https://www.selleckchem.com/products/tpca-1.html Upon cleavage by inflammasome-associated caspases, the N-terminal domain of GSDMD forms membrane pores that promote cytolysis. Numerous proteins promote GSDMD cleavage, but none are known to be required for pore formation after GSDMD cleavage. Herein, we report a forward genetic screen that identified the Ragulator-Rag complex as being necessary for GSDMD pore formation and pyroptosis in macrophages. Mechanistic analysis revealed that Ragulator-Rag is not required for GSDMD cleavage upon inflammasome activation but rather promotes GSDMD oligomerization in the plasma membrane. Defects in GSDMD oligomerization and pore formation can be rescued by mitochondrial poisons that stimulate reactive oxygen species (ROS) production, and ROS modulation impacts the ability of inflammasome pathways to promote pore formation downstream of GSDMD cleavage. These findings reveal an unexpected link between key regulators of immunity (inflammasome-GSDMD) and metabolism (Ragulator-Rag).The coronavirus disease 2019 (COVID-19) pandemic underscores the need to better understand animal-to-human transmission of coronaviruses and adaptive evolution within new hosts. We scanned more than 182,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes for selective sweep signatures and found a distinct footprint of positive selection located around a non-synonymous change (A1114G; T372A) within the spike protein receptor-binding domain (RBD), predicted to remove glycosylation and increase binding to human ACE2 (hACE2), the cellular receptor. This change is present in all human SARS-CoV-2 sequences but not in closely related viruses from bats and pangolins. As predicted, T372A RBD bound hACE2 with higher affinity in experimental binding assays. We engineered the reversion mutant (A372T) and found that A372 (wild-type [WT]-SARS-CoV-2) enhanced replication in human lung cells relative to its putative ancestral variant (T372), an effect that was 20 times greater than the well-known D614G mutation. Our findings suggest that this mutation likely contributed to SARS-CoV-2 emergence from animal reservoirs or enabled sustained human-to-human transmission.This cross-sectional study aimed to determine whether there is an association between objectively assessed physical activity (PA) and health-related quality of life (HRQoL) in children with CHD.
From September 2017 to January 2021, 343 children with CHD (12.1 ± 3.3 years, 135 girls) provided valid PA data after a 7-day objective PA assessment. PA was evaluated as average daily steps and moderate-to-vigorous physical activity (MVPA) minutes assessed via wearable bracelet Garmin vivofit Jr. These children also completed the KINDL - a 24 Likert-scaled item questionnaires assessing HRQoL in the six dimensions physical well-being, emotional well-being, self-esteem, family, friends and everyday functioning.
Daily Steps (r=0.166, P=.003) and daily MVPA minutes (r=0.134, P=.017,) were both correlated to total KINDL score. Furthermore, both steps and MVPA were associated with the subscales physical well-being (steps r=0.165 p=.003; MVPA r=0.129, P=.022), friends (steps r=0.210, P &lt; .001, MVPA r=0.179, P=.001), steps, and to everyday functioning (r=0.142, P=.012). Logistic regression showed each MVPA minute increase conferred to a 1% increase in reporting better HRQoL (OR 1.009 [95% CI 1.002 - 1.017], P=.019).
PA was positively associated with HRQoL in children with CHD. Patients who move more are more likely to report better HRQoL. While the magnitude of this association needs to be further understood, continuous encouragement towards more PA seems to be crucial in a holistic approach to medical aftercare in children with CHD.
PA was positively associated with HRQoL in children with CHD. Patients who move more are more likely to report better HRQoL. While the magnitude of this association needs to be further understood, continuous encouragement towards more PA seems to be crucial in a holistic approach to medical aftercare in children with CHD.